AD is a serious neurodegenerative brain disease affecting mainly older people. The disease starts to manifest with memory decline, learning disorders, behavioral changes, impairment in orientation in time and space, loss of autonomic functions, finally results in complete dementia. The death comes on average 9 years after diagnosis.
Histopathologically, AD is characterized by two hallmarks in brain: intracelullar neurofibrilary tangles formed by hyperphosphorylated Tau protein and extracellular senile plaques of beta peptide.
Prolactin releasing peptide (PrRP) was discovered at the end of 20th century. Naturally two isoforms of PrRP can be found in organism: peptide containing 31 amino acids (PrRP/1-31/; PrRP31) or 20 amino acids (PrRP/12-31/; PrRP20), its amino acid composition also exhibits small differences in various species (human, rat, bovine) (Hinuma et al., 1998).
PrRP is produced in neurons of many brain regions, mainly in medulla oblongata (in nucleus tractus solitarius and ventrolateral reticular nucleus), and hypothalamus (in paraventricular and dorsomedial nuclei) (Maruyama et al., 1999; Lee et al., 2000), less in pituitary gland, and amygdala. In the periphery PrRP can be found in adrenal medulla, testis, pancreas, and small and large intestines.
PrRP receptor, GPR10, is extensively expressed in the whole brain; it can be found in anterior pituitary, amygdala, hypothalamus, brainstem, and medulla oblongata. In the periphery GPR10 can be found in adrenal medulla, and significantly increased expression was observed in human and rat pancreas.
Subsequently, new modified analogs of neuropeptides PrRP31 and PrRP20 were synthesized, with changes in amino acid chain, lipidated with fatty acid (e.g. myristoylated or palmitoylated) at the N-terminus, however, for use in regulating food intake (WO2014/009808) and regulating blood glucose levels (US 2016/228563).
Neuropeptides PrRP31 and PrRP20 and their analogs lipidated either at N-terminus or in the middle of their peptide chain showed higher affinity to endogenous GPR10 receptor also in in vitro experiments (WO2014/009808, US 2016/228563).
Lipidated neuropeptides based on PrRP20 and PrRP31 and their analogs and their activities are known also from WO 2009/033668; Tachibana T. et al: Physiology and Behavior, vol. 120, 2013, 40-45; Takayanagi Y. et al.: Journal of Clinical Investigation, vol. 118, 2008, 4014-4024.
Nowadays, drugs slowing the AD progression and improving cognitive functions are used. These are inhibitors of acetylcholinesterase, which increase acetylcholine concentration in the brain and inhibitors of N-methyl-D-aspartate receptors (e.g. memantin).
Because of the high incidence of insulin resistance in AD patients, it is not possible to use insulin as an AD treatment. It is hypothesized that agents increasing insulin sensitivity, such as metformim, insulin secretagogues such as glucagon-like peptide-1 (GLP-1), gastric-inhibitory peptide (GIP) and their analogs could act as AD treatment.
There is a need to provide further substances with neuroprotective effect which could be useful in the treatment of neurodegenerative diseases.